# Antagonists of CRMP2 Phosphorylation for Chemotherapy-Induced Peripheral Neuropathy

> **NIH NIH R61** · UNIVERSITY OF FLORIDA · 2022 · $902,822

## Abstract

SUMMARY
Identification of new targets and mechanisms underlying neuropathic pain is critical to developing new target-
specific medications for better neuropathic pain management. The misuse of and addiction to opioids—including
prescription pain relievers, heroin, and synthetic opioids such as fentanyl—is a serious national crisis that affects
public health as well as social and economic welfare. The current opioid crisis requires novel approaches to
chronic pain management. Our proposal leverages a unique finding, originating from the laboratory of Dr. Rajesh
Khanna (originally at the University of Arizona and now at the University of Florida), that peripheral nerve injury-
induced upregulation of an axonal guidance phosphoprotein collapsin response mediator protein 2 (CRMP2)
and the N-type voltage-gated calcium (CaV2.2) as well as the NaV1.7 voltage-gated sodium channel, correlates
with the development of neuropathic pain. Leveraging a pocket on the surface of CRMP2, amenable for in silico
screening, the PI’s laboratory performed a virtual screen of nearly 0.3 million compounds (diverse small
molecules and natural products). Several of the top 21 ‘hit’ compounds from this screen have been validated in
in vitro and in vivo experiments, providing experimental proof of our in-silico predictions. Predicted physico-
chemical properties of the hit series fall within ranges of lead- or ‘drug-like’ molecules. We have assembled a
diverse multidisciplinary team to test the hypothesis that inhibiting CRMP2 phosphorylation associated with
sodium and calcium channel activities to decrease nociceptor activity culminates in reduced pain. Our Specific
Aims, guided by quantitative goals, are: (1) to profile CRMP2 phosphorylation antagonists for their ability to: (i)
bind CRMP2 and (ii) block its phosphorylation by Cdk5 and (iii) inhibit calcium and sodium currents in sensory
neurons using whole-cell electrophysiology with a smaller subset being tested in male/female human DRGs; (2)
profile CRMP2 phosphorylation antagonists for ADME pharmacokinetic properties and off-target effects on
GPCRs, kinases, ion channels and alternative known pain targets, including opioid receptors; (3) characterize
the best CRMP2 phosphorylation antagonists for in vivo efficacy in rodents using a phenotypic screen and spared
nerve injury (SNI) model of neuropathic pain and explore the potential of phosphorylated CRMP2 as a marker of
target engagement; (4) validate optimized CRMP2 phosphorylation antagonists in a mouse model of
chemotherapy-induced peripheral neuropathy (CIPN) and assess potential reward and/or aversion. At the end
of our study, we expect to have at least one lead series for optimization with the goal of developing a selective
and efficacious CRMP2 phosphorylation inhibitor for neuropathic pain with minimal side effects or addiction
potential.

## Key facts

- **NIH application ID:** 11126912
- **Project number:** 7R61NS126026-02
- **Recipient organization:** UNIVERSITY OF FLORIDA
- **Principal Investigator:** Rajesh Khanna
- **Activity code:** R61 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $902,822
- **Award type:** 7
- **Project period:** 2022-09-15 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11126912

## Citation

> US National Institutes of Health, RePORTER application 11126912, Antagonists of CRMP2 Phosphorylation for Chemotherapy-Induced Peripheral Neuropathy (7R61NS126026-02). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/11126912. Licensed CC0.

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